{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:43:27Z","timestamp":1784249007021,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute of the National Institutes of Health","award":["R01CA226756"],"award-info":[{"award-number":["R01CA226756"]}]},{"name":"National Cancer Institute of the National Institutes of Health","award":["P30CA046592"],"award-info":[{"award-number":["P30CA046592"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Tubo-ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy, usually diagnosed at an advanced stage due to the lack of early symptoms and biomarkers. Contraceptive hormone use is associated with a reduced risk of HGSC, but the relative contributions of natural versus synthetic progestins, and their interaction with estrogens, are poorly understood. Methods: We evaluated the chemo-preventive efficacy of a synthetic progestin medroxyprogesterone acetate (MPA), progesterone (P4), and combined 17\u03b2-estradiol-progesterone (E2 + P4) in a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on the conditional inactivation of one or both alleles of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN-het and BPRN-homo mice, respectively). Mice received hormones or placebo via slow-release pellets implanted subcutaneously. After induction of tumor formation, the mice were monitored for tumor development, progression, and survival. Tumor incidence was assessed histologically, and hormone effects were further explored via RNA-seq analysis of oviductal tissues. Results: MPA significantly reduced HGSC incidence and delayed tumor progression compared to the placebo, P4, and P4 + E2 in both BPRN-homo and BPRN-het mice, with up to 78% tumor-free survival in the MPA-treated BPRN-het cohort. P4 monotherapy did not provide significant protection vs. the placebo, but the effects of P4 could have been impacted by a failure to achieve sustained release of the hormone beyond 4\u20138 weeks. The E2 + P4 combination accelerated tumorigenesis and reduced survival (p &lt; 0.0001 in BPRN-homo and p = 0.0004 in BPRN-het mice). MPA did not affect tumorigenesis in a colon cancer GEMM, or the growth of mouse HGSC-derived cells in vivo, suggesting the role of MPA in the early stages of HGSC development. Gene expression analyses showed that P4 and MPA downregulated cholesterol homeostasis, early and late estrogen response, and epithelial\u2013mesenchymal transition pathways, though only MPA afforded tumor protection. Conclusions: These findings demonstrate that a synthetic progestin, specifically MPA, confers robust protection against HGSC development, while a combination including E2 (E2 + P4) increases risk. This work also illustrates how HGSC GEMMs can be used to compare the chemo-preventive effects of various synthetic progestins on HGSC development in order to prioritize the most effective ones for use in preventing HGSC in both general and high-risk populations.<\/jats:p>","DOI":"10.3390\/cancers17213456","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:02:01Z","timestamp":1761670921000},"page":"3456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Medroxyprogesterone Acetate Inhibits Tumorigenesis in Mouse Models of Oviductal High-Grade Serous Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-7336","authenticated-orcid":false,"given":"Yali","family":"Zhai","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-738X","authenticated-orcid":false,"given":"Karan","family":"Bedi","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maranne E.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste Leigh","family":"Pearce","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-1199","authenticated-orcid":false,"given":"Malcolm C.","family":"Pike","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Fearon","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0500-9998","authenticated-orcid":false,"given":"Kathleen R.","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"216057","DOI":"10.1016\/j.canlet.2023.216057","article-title":"Molecular characteristics and clinical behaviour of epithelial ovarian cancers","volume":"555","author":"Hollis","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral, V., Doll, R., Hermon, C., Peto, R., and Reeves, G. (2008). Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet, 371, 303\u2013314.","DOI":"10.1016\/S0140-6736(08)60167-1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/AOG.0b013e318291c235","article-title":"Oral contraceptive pills as primary prevention for ovarian cancer: A systematic review and meta-analysis","volume":"122","author":"Havrilesky","year":"2013","journal-title":"Obs. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1093\/aje\/152.3.233","article-title":"Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions","volume":"152","author":"Ness","year":"2000","journal-title":"Am. J. Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.20892\/j.issn.2095-3941.2016.0084","article-title":"Epidemiology of ovarian cancer: A review","volume":"14","author":"Reid","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1200\/JCO.2016.66.8178","article-title":"Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium","volume":"34","author":"Wentzensen","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/cncr.23956","article-title":"Increased ovarian cancer risk associated with menopausal estrogen therapy is reduced by adding a progestin","volume":"115","author":"Pearce","year":"2009","journal-title":"Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1158\/1055-9965.EPI-20-1355","article-title":"Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins","volume":"30","author":"Phung","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31993","DOI":"10.1073\/pnas.2013595117","article-title":"Targeting progesterone signaling prevents metastatic ovarian cancer","volume":"117","author":"Kim","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/path.4927","article-title":"High-grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease","volume":"243","author":"Zhai","year":"2017","journal-title":"J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1158\/0008-5472.CAN-19-2558","article-title":"Murine Oviductal High-Grade Serous Carcinomas Mirror the Genomic Alterations, Gene Expression Profiles, and Immune Microenvironment of Their Human Counterparts","volume":"80","author":"McCool","year":"2020","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.ygyno.2022.03.030","article-title":"Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma","volume":"165","author":"Hou","year":"2022","journal-title":"Gynecol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1158\/0008-5472.CAN-21-0106","article-title":"Altering the Microbiome Inhibits Tumorigenesis in a Mouse Model of Oviductal High-Grade Serous Carcinoma","volume":"81","author":"Chen","year":"2021","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e184115","DOI":"10.1172\/JCI184115","article-title":"SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction","volume":"135","author":"Feng","year":"2025","journal-title":"J. Clin. Invest."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1038\/nprot.2006.328","article-title":"Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients","volume":"1","author":"Shepherd","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet J."},{"key":"ref_17","unstructured":"Andrews, S. FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.12688\/f1000research.15931.1","article-title":"FastQ Screen: A tool for multi-genome mapping and quality control","volume":"7","author":"Wingett","year":"2018","journal-title":"F1000Research"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, B., and Dewey, C.N. (2011). RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-323"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"bvac100","DOI":"10.1210\/jendso\/bvac100","article-title":"Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer","volume":"6","author":"Johansson","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2011). Integrated genomic analyses of ovarian carcinoma. Nature, 474, 609\u2013615.","DOI":"10.1038\/nature10166"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1200\/JCO.23.01918","article-title":"Menopausal Hormone Therapy and Ovarian and Endometrial Cancers: Long-Term Follow-Up of the Women\u2019s Health Initiative Randomized Trials","volume":"42","author":"Chlebowski","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1097\/EDE.0000000000001175","article-title":"Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer: A Complicated Relationship Explored","volume":"31","author":"Lee","year":"2020","journal-title":"Epidemiology"},{"key":"ref_26","unstructured":"Sathe, A., Patel, P., and Gerriets, V. (2025). Medroxyprogesterone. StatPearls, StatPearls Publishing."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1158\/1940-6207.CAPR-21-0324","article-title":"Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer","volume":"15","author":"Nelson","year":"2022","journal-title":"Cancer Prev. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1530\/ERC-18-0132","article-title":"Simvastatin interferes with cancer \u2018stem-cell\u2019 plasticity reducing metastasis in ovarian cancer","volume":"25","author":"Kato","year":"2018","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1002\/ijc.31758","article-title":"Statin Therapy and Association with Ovarian Cancer risk in the New England Case Control (NEC) Study","volume":"144","author":"Akinwunmi","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Di Zazzo, E., Galasso, G., Giovannelli, P., Di Donato, M., Bilancio, A., Perillo, B., Sinisi, A.A., Migliaccio, A., and Castoria, G. (2019). Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer. Cancers, 11.","DOI":"10.3390\/cancers11101418"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jsbmb.2006.09.039","article-title":"Estrogen promotes reversible epithelial-to-mesenchymal-like transition and collective motility in MCF-7 breast cancer cells","volume":"104","author":"Waltz","year":"2007","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"446","DOI":"10.4048\/jbc.2023.26.e37","article-title":"Estradiol-Induced Epithelial to Mesenchymal Transition and Migration Are Inhibited by Blocking c-Src Kinase in Breast Cancer Cell Lines","volume":"26","year":"2023","journal-title":"J. Breast Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13058-018-0996-9","article-title":"Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression","volume":"20","author":"Wang","year":"2018","journal-title":"Breast Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1210\/en.2006-1120","article-title":"Estrogen decrease in tight junctional resistance involves matrix-metalloproteinase-7-mediated remodeling of occludin","volume":"148","author":"Gorodeski","year":"2007","journal-title":"Endocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s10549-006-9335-4","article-title":"MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells","volume":"102","author":"Nilsson","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1186\/s12967-025-06447-w","article-title":"Matrix metalloproteinase-driven epithelial-mesenchymal transition: Implications in health and disease","volume":"23","author":"Radisky","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s43188-021-00100-6","article-title":"Estrogen exposure causes the progressive growth of SK-Hep1-derived tumor in ovariectomized mice","volume":"38","author":"Oh","year":"2022","journal-title":"Toxicol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1210\/en.2009-0602","article-title":"17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer","volume":"151","author":"Laviolette","year":"2010","journal-title":"Endocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.steroids.2003.08.003","article-title":"All progestins are not created equal","volume":"68","author":"Stanczyk","year":"2003","journal-title":"Steroids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1210\/er.2012-1008","article-title":"Progestogens used in postmenopausal hormone therapy: Differences in their pharmacological properties, intracellular actions, and clinical effects","volume":"34","author":"Stanczyk","year":"2013","journal-title":"Endocr. Rev."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:18:15Z","timestamp":1761671895000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":40,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cancers17213456"],"URL":"https:\/\/doi.org\/10.3390\/cancers17213456","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]}}}